RESUMO
Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD.Flt23k.NP in mice. The effect of various doses was determined using fluorescein angiography and optical coherence tomography to evaluate CNV leakage and volume. Efficacy was determined by the rate of inhibition of CNV volume at 2 weeks post-treatment. RGD.Flt23k.NP had peak efficacy at a dose range of 30-60 µg pFlt23k/mouse. Using the lower dose (30 µg pFlt23k/mouse), RGD.Flt23k.NP safety was determined both in single-dose groups and in repeat-dose (three times) groups by measuring body weight, organ weight, hemoglobin levels, complement C3 levels, and histological changes in vital organs. Neither toxicity nor inflammation from RGD.Flt23k.NP was detected. No side effect was detected on visual function. Thus, systemic RGD.Flt23k.NP may be an alternative to standard intravitreal anti-VEGF therapy for the treatment of neovascular AMD.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neovascularização de Coroide/terapia , Portadores de Fármacos , Degeneração Macular/terapia , Plasmídeos/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Corioide/irrigação sanguínea , Corioide/metabolismo , Corioide/patologia , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Regulação da Expressão Gênica , Hemoglobinas/metabolismo , Humanos , Injeções Intravenosas , Injeções Intravítreas , Lasers , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Plasmídeos/química , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Background: MRI-guided fusion biopsy is increasingly utilized over systematic 12-core biopsy for men with MRI-visible prostate lesions. Patients and Methods: Patients with MRI visible lesions who underwent MRI-guided fusion and systematic 12-core biopsy from 2016-2020 in the Intermountain Healthcare (IHC) system were consecutively analyzed. This was in the setting of a continuous quality assurance initiative among the reading radiologists. Primary outcome was prostate cancer (PCa) detection defined by Gleason grade group (GGG) 1 or higher. Clinically significant cancer (CSC) was defined as GGG 2 or higher. Patients were stratified by biopsy date, 2016-2017 and 2018-2021, and lesions were stratified by PI-RADS v2 category. Results: A total of 184 patients with 324 MRI-detectable lesions underwent both biopsy modalities in the IHC system from 2016 to 2021. CSC was detected in 23.5% of MRI-guided fusion biopsies. Comparing PI-RAD v2 categories 1-3 to categories 4-5, rate of CSC was 10% and 42% respectively. MRI-guided fusion and systematic 12-core biopsies were concordant for PCa in 77% of men and CSC in 83%. MRI-guided fusion biopsy detected PCa in 26/103 and CSC in 20/131 men in whom systematic 12-core biopsy was negative. Systematic 12-core biopsy detected PCa in 17/94 and CSC in 11/122 men in whom MRI-guided fusion was negative. Conclusions: Omitting MRI-guided fusion or systematic 12-core biopsy would have resulted in underdiagnosis of CSC in 11% or 6% of patients respectively. Combining biopsies increased detection rate of CSC. This was in the setting of a continuous quality assurance program at a large community-based hospital.
RESUMO
Purpose: We determine whether intravitreal angiopoietin-1 combined with the short coiled-coil domain of cartilage oligomeric matrix protein by adeno-associated viral serotype 2 (AAV2.COMP-Ang1) delivery following the onset of vascular damage could rescue or repair damaged vascular beds and attenuate neuronal atrophy and dysfunction in the retinas of aged diabetic mice. Methods: AAV2.COMP-Ang1 was bilaterally injected into the vitreous of 6-month-old male Ins2Akita mice. Age-matched controls consisted of uninjected C57BL/6J and Ins2Akita males, and of Ins2Akita males injected with PBS or AAV2.REPORTER (AcGFP or LacZ). Retinal thickness and visual acuity were measured in vivo at baseline and at the 10.5-month endpoint. Ex vivo vascular parameters were measured from retinal flat mounts, and Western blot was used to detect protein expression. Results: All three Ins2Akita control groups showed significantly increased deep vascular density at 10.5 months compared to uninjected C57BL/6J retinas (as measured by vessel area, length, lacunarity, and number of junctions). In contrast, deep microvascular density of Ins2Akita retinas treated with AAV2.COMP-Ang1 was more similar to uninjected C57BL/6J retinas for all parameters. However, no significant improvement in retinal thinning or diabetic retinopathy-associated visual loss was found in treated diabetic retinas. Conclusions: Deep retinal microvasculature of diabetic Ins2Akita eyes shows late stage changes consistent with disorganized vascular proliferation. We show that intravitreally injected AAV2.COMP-Ang1 blocks this increase in deep microvascularity, even when administered subsequent to development of the first detectable vascular defects. However, improving vascular normalization did not attenuate neuroretinal degeneration or loss of visual acuity. Therefore, additional interventions are required to address neurodegenerative changes that are already underway.